Spantide I is an analogue of substance P (SP) and a selective NK1 receptor antagonist with Ki values of 230nM and 8150nM for NK1 and NK2 receptor, respectively [1]. The NK1 is broadly expressed in the eye, in both ocular and non-ocular cells, such as leukocytes and neurons [2]. Spantide I provides an approach to reduce type 1 and enhance the type 2 cytokine IL-10 in the infected cornea, leading to a significant reduction in corneal perforation [3].
In vitro, Spantide I (10μM) treatment of regulatory T cells (Tregs) for 48 hours reversed the reduction in Foxp3, CTLA-4, and PD-1 expression levels caused by SP treatment. At the same time, Spantide I blocked the SP signal transduction and inhibited the decrease in TGF-β levels observed in SP-induced Tregs cells [4]. Treating TG neurons isolated from dry eye disease (DED) mice with a culture medium containing Spantide I (2μM) for 24 hours significantly reduced the proliferation of vascular endothelial cells (VEC) co-cultured with the TG neurons, and also eliminated the promotion of tube formation by the VECs [5].
In vivo, treating mice with Spantide I (36μg/mouse/day; i.p.) for 7 days significantly reduced the number of corneal perforations, bacterial count, and neutrophil count in mice infected with Pseudomonas aeruginosa, and also downregulated the mRNA levels of type I cytokines (such as IFN-γ) as well as MIP-2, IL-6, TNF-α, and IL-1β [3]. Treating mice exposed to UVR-B with Spantide I (72μg/mouse/day; i.p.) for 7 days significantly reduced the expression of NKR-1 in the corneas. Spantide I has a protective effect after corneal injury induction [6].
References:
[1] Zubrzycka M, Janecka A, Traczyk WZ. Comparison of antagonistic properties of substance P analogs, spantide I, II and III, on evoked tongue jerks in rats. Endocr Regul. 2000 Mar;34(1):13-8.
[2] Demirsoy I H, Ferrari G. The NK-1 receptor signaling: distribution and functional relevance in the eye[J]. Receptors, 2022, 1(1): 98-111.
[3] Hazlett LD, McClellan SA, Barrett RP, Liu J, Zhang Y, Lighvani S. Spantide I decreases type I cytokines, enhances IL-10, and reduces corneal perforation in susceptible mice after Pseudomonas aeruginosa infection. Invest Ophthalmol Vis Sci. 2007 Feb;48(2):797-807.
[4] Taketani Y, Marmalidou A, Dohlman TH, et al. Restoration of Regulatory T-Cell Function in Dry Eye Disease by Antagonizing Substance P/Neurokinin-1 Receptor. Am J Pathol. 2020;190(9):1859-1866.
[5] Liu L, Dana R, Yin J. Sensory neurons directly promote angiogenesis in response to inflammation via substance P signaling. FASEB J. 2020;34(5):6229-6243.
[6] Gross J, Wegener AR, Kronschläger M, Schönfeld CL, Holz FG, Meyer LM. UVR-B-induced NKR-1 Expression in Ocular Tissues is blocked by Substance P Receptor Antagonist Fosaprepitant in the Exposed as well as Unexposed Partner Eye. Ocul Immunol Inflamm. 2021;29(5):963-975.
Spantide I是一种与P物质（SP）类似的具有选择性的NK1受体拮抗剂，其对NK1和NK2受体的Ki值分别为230nM和8150nM [1]。NK1R在眼睛中广泛分布，存在于眼部细胞以及非眼部细胞中，例如白细胞和神经元 [2]。Spantide I为降低感染角膜中的类型1细胞因子并增强类型2细胞因子IL-10提供了一种方法，从而显著减少了角膜穿孔的发生 [3]。
在体外，Spantide I（10μM）处理调节性T细胞（Tregs）48小时，逆转了SP处理的细胞中Foxp3、CTLA-4和PD-1表达水平的降低。同时，Spantide I阻断SP信号传导抑制了SP诱导的Tregs细胞中TGF-β水平的减少 [4]。用含Spantide I（2μM）的培养基处理从干眼症（DED ）小鼠分离的TG神经元24小时，显著降低了与TG神经元共培养的血管内皮细胞（VEC）增殖，也消除了对VEC管形成的促进 [5] 。
在体内，通过Spantide I（36μg/只/天；i.p.）治疗7天，显著减少了感染铜绿假单胞菌的小鼠角膜穿孔的数量、细菌数量以及中性粒细胞的数量，并且还下调了I型细胞因子（如IFN-γ）以及MIP-2、IL-6、TNF-α和IL-1β的mRNA水平 [3]。通过Spantide I（72μg/只/天；i.p.）治疗7天，显著减少了暴露于UVR-B小鼠角膜中NKR-1的表达。Spantide I在角膜诱导损伤后具有保护作用 [6]。